In long-term studies, we have discovered important associations of impaired cognitive development, physical fitness, and growth with early childhood diarrhea and malnutrition in favela (shantytown) children in Northeast Brazil. Having found that an "Alzheimer's-like" deficit in higher executive function and semantic fluency were most affected, we then found a striking association of the "Alzheimer's gene," APOE4, with protection from the cognitive developmental impairments. Hence we postulate that early childhood diarrhea and its consequent malnutrition have their greatest impact via lasting impairment on cognitive development effects that are accentuated in individuals lacking the "protective" APOE4 allele and that specific micronutrient interventions can ameliorate this effect. In order to directly test our hypothesis that intestinal and cognitive impairments involve ApoE and that specific micronutrients can ameliorate these effects, and to examine potential mechanisms involved, we have established murine models of early malnutrition, growth, and cognitive development in both wild-type and APOE-knockout mice in our collaborations at the Federal University of Ceara (UFC) in Brazil and at the University of Virginia (UVa) respectively. Furthermore, with a synergistic new collaboration with colleagues at Duke University, we can specifically examine effects of APOE4 using human APOE4 targeted replacement "knock-in" mice to "close the loop" on our hypothesis and directly assess whether and how apoE4 is protective against intestinal and cognitive effects of malnutrition, studies that will have direct implications for the optimal health and development of children throughout developing areas. Hence our specific aims are to define the effects of malnutrition and specific micronutrients on intestinal, brain, and cognitive development in a murine model using outbred and inbred wild-type, ApoE knock-out (ko), and human ApoE4 targeted replacement "knock-in" C57BI mice. We will define the effects on intestinal and brain histology and maturation using immunohistochemical methods and studies of developmental milestones and behavioral ontogeny. We will seek to identify potential mechanisms of these effects in the intestine and brain including studies of IGF-1, and will examine the effects of glutamine, zinc, and arginine interventions.